Indexing Effects of Copy Number Variation on Genes Involved in Developmental Delay

Mohammed Uddin, Giovanna Pellecchia, Bhooma Thiruvahindrapuram, Lia D'Abate, Daniele Merico, Ada Chan, Mehdi Zarrei, Kristiina Tammimies, Susan Walker, Matthew J. Gazzellone, Thomas Nalpathamkalam, Ryan K.C. Yuen, Koenraad Devriendt, Géraldine Mathonnet, Emmanuelle Lemyre, Sonia Nizard, Mary Shago, Ann M. Joseph-George, Abdul Noor, Melissa T. CarterGrace Yoon, Peter Kannu, Frédérique Tihy, Erik C. Thorland, Christian R. Marshall, Janet A. Buchanan, Marsha Speevak, Dimitri J. Stavropoulos, Stephen W. Scherer

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


A challenge in clinical genomics is to predict whether copy number variation (CNV) affecting a gene or multiple genes will manifest as disease. Increasing recognition of gene dosage effects in neurodevelopmental disorders prompted us to develop a computational approach based on critical-exon (highly expressed in brain, highly conserved) examination for potential etiologic effects. Using a large CNV dataset, our updated analyses revealed significant (P < 1.64 × 10-15) enrichment of critical-exons within rare CNVs in cases compared to controls. Separately, we used a weighted gene co-expression network analysis (WGCNA) to construct an unbiased protein module from prenatal and adult tissues and found it significantly enriched for critical exons in prenatal (P < 1.15 × 10-50, OR = 2.11) and adult (P < 6.03 × 10-18, OR = 1.55) tissues. WGCNA yielded 1,206 proteins for which we prioritized the corresponding genes as likely to have a role in neurodevelopmental disorders. We compared the gene lists obtained from critical-exon and WGCNA analysis and found 438 candidate genes associated with CNVs annotated as pathogenic, or as variants of uncertain significance (VOUS), from among 10,619 developmental delay cases. We identified genes containing CNVs previously considered to be VOUS to be new candidate genes for neurodevelopmental disorders (GIT1, MVB12B and PPP1R9A) demonstrating the utility of this strategy to index the clinical effects of CNVs.

Original languageEnglish (US)
Article number28663
JournalScientific reports
StatePublished - Jul 1 2016

ASJC Scopus subject areas

  • General


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